CN101007844A - Synthetic peptides and methods for treating cancer invasion and metastasis - Google Patents

Synthetic peptides and methods for treating cancer invasion and metastasis Download PDF

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CN101007844A
CN101007844A CNA2007100054389A CN200710005438A CN101007844A CN 101007844 A CN101007844 A CN 101007844A CN A2007100054389 A CNA2007100054389 A CN A2007100054389A CN 200710005438 A CN200710005438 A CN 200710005438A CN 101007844 A CN101007844 A CN 101007844A
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马蒂亚斯·拉特
施朗·奈克
阿莱克斯圣德拉·尼德兹维克
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Abstract

The present invention relates to synthetic peptides of the invention comprises PRKPKWDK (SEQ ID: 2) peptide corresponding to amino acids of 85 to 92 of the matrix metalloproteinase (MMP-2), and fragments, analogs and homologs to SEQ ID:2). The invention also relates to the uses of such peptides as inhibitory of human cancer invasion and metastasis and further to the therapeutic use in preventing and and treating cancer and other pathological conditions related to the degradation of extracellular matrix by MMPs.

Description

Synthetic peptide and be used to prevent and treat the purposes of invasive cancer and transfer
The application is the dividing an application that be on January 23rd, 2003, denomination of invention the applying date for the Chinese invention patent application No.03802689.9 of " synthetic peptide and be used to prevent and treat the purposes of invasive cancer and transfer ".
Invention field
The present invention relates to show to the active synthetic peptide of the inhibition of invasive cancer and transfer.Peptide of the present invention comprises the amino acid whose PRKPKWDK of 85-92 (SEQ ID:2) peptide corresponding to matrix metalloproteinase-2 (MMP-2), and the fragment of SEQ ID:2, analogue and homologue.The invention still further relates to this peptide uses with the treatment in treatment cancer and other pathological condition relevant with MMP degraded extracellular matrix as the purposes of human cancer invasion and attack and the inhibition that shifts and in prevention.
Background of invention
Multiple pathological condition comprises that neoplastic disease is relevant with the active increase of matrix metalloproteinase (MMP).MMP is a cocainine propylhomoserin proteolytic enzyme, its extracellular matrix (ECM) of degrading.MMP is secreted in extracellular matrix with its zymogen forms.Activated, mmp enzyme becomes to be had activity and digests ECM, and this process is shown in the cancer metastasis and plays a major role.
They are at least some the proteolytic enzyme members in the MMP family, and comprise MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13.In cancer, MMP-2 participates in primary tumo(u)r growth and metastases.This specific MMP can digest collagen and other extracellular matrix (ECM) albumen, as the prerequisite of cancer diffusion invasion and attack to take place and shift.
Although carried out a large amount of effort, continue to need a kind of nontoxic therapeutical agent that can effectively block the MMP mediation, thereby reduce the diffusion of cancer and other disease the digestion of ECM at design and test carcinostatic agent.
Summary of the invention
The present invention relates to effectively to block the synthetic peptide of cancer cells invasion and attack.The benefit of these materials and antibody thereof is the effectiveness in the clinical application that is used for blocking invasive cancer and transfer.
An object of the present invention is to provide the synthetic oligopeptide of effective blocking-up invasive cancer and cancer metastasis, it has and the similar aminoacid sequence of the specific amino acids sequence (85-92) of matrix metalloproteinase 2 sequences.
An object of the present invention is to provide the synthetic peptide that is used to block invasive cancer and transfer, it has aminoacid sequence PRKPKWEDK.
Another object of the present invention is to adopt the method for preventing and treating Cancerous disease as the disclosed synthetic peptide of the application.This embodiment be that synthetic peptide with significant quantity is used to realize the blocking-up to invasive cancer and transfer on the other hand.
Another object of the present invention provides the oligopeptides with PRKPKWDK (SEQ.ID.No.2).
Preferably, this oligopeptides is about 20 residues of about 6-.Most preferably, this oligopeptides is about 10 residues of about 8-.
Preferably, the concentration range of synthetic peptide is from 1 μ M to 500 μ M.Most preferably, the concentration range of synthetic peptide is from 50 μ M to 200 μ M.
Another object of the present invention is the immunogenicity oligopeptides that is included in the pharmaceutical composition, and described pharmaceutical composition comprises pharmaceutically acceptable carrier and described oligopeptides.This oligopeptides can be used as vaccine.The pharmaceutical composition that comprises oligopeptides can be used for inducing at comprising and has the oligopeptides sequence (SEQ.ID. for example
The proteic immunne response of epi-position 2).
Another object of the present invention be described composition and method in vivo with external realization.
The invention provides the synthetic oligopeptide that has with the similar aminoacid sequence of people MMP-2.
The present invention also provides the modification of the oligopeptides of blocking the cancer cells invasion and attack and shift being carried out by the one or more amino-acid residues that omit the N-end.
The invention provides the modification of the oligopeptides of blocking the cancer cells invasion and attack and shift being carried out by the one or more amino-acid residues that omit the C-end.
The invention provides by omitting the modification that N-one or more amino-acid residues terminal and the C-end are attacked the blocking-up cancer cells and the oligopeptides of transfer carries out.
The invention provides electric charge and the polarity of not considering to replace residue by replacing the one or more amino-acid residues among given sequence, the modification that the oligopeptides that the blocking-up cancer cells is attacked and shifted carries out.
The invention provides by using and have similar electric charge and/or the one or more amino-acid residues of polar radical amino acid replacement among given sequence, the modification that the oligopeptides that the blocking-up cancer cells is attacked and shifted carries out.
The invention provides the modification of the invasion and attack of blocking-up cancer cells and the oligopeptides that shifts being carried out by the one or more amino-acid residues that are omitted among the given sequence.
The invention provides by two or more described modifications the modification that the oligopeptides that the blocking-up cancer cells is attacked and shifted carries out.
The invention provides by repeating oligopeptides sequence one or many, each in them is covalently bond to one or more oligopeptides and repeats, and the modification that the oligopeptides that the blocking-up cancer cells is attacked and shifted carries out.
Another object of the present invention is to use synthetic peptide to generate antibody as immunogen, thereby makes the antibody of this generation can effectively block invasive cancer and transfer.
The invention provides one or more described oligopeptides and go up metabolism or interactional prevention or the therepic use that acceptable manner directly and competitively weakens or block MMP-2 by the intravenously application or with the another kind treatment.
The invention provides metabolism or interactional prevention or therepic use that one or more described oligopeptides weaken or block MMP indirectly, by subcutaneous application or with another kind of acceptable manner with them as vaccine administration to stimulate antigen-specific immune responses, its metabolism that can partially or completely block MMP5 interacts.Embodiment preferred comprises MMP-2.
The invention provides the prevention and the therepic use of one or more described oligopeptides, thereby wherein oligopeptides is coupled to haptens and replys with enhancing immunity and increase treatment and render a service.
The invention provides the prevention or the therepic use of one or more described oligopeptides, its function stops specifically as the feedback regulation thing or reduces the synthetic ratio of MMP-2 albumen at cell levels.
The oligopeptides that the invention provides one or more cancer cells capable of blocking invasion and attack and shift to produce specific antibody, is used to diagnose the disease that relates to MMP-2 as vaccine, or the progress of this disease of clinical monitoring or disappear.
The oligopeptides that the invention provides one or more blocking-up cancer cells invasion and attack and shift is used to prevent or treat the purposes of cancer.
The purposes of the oligopeptides that the invention provides one or more blocking-up cancer cells invasion and attack and shift, wherein these oligopeptides can be used as vaccine, are applied to the patient as injection, transfusion, inhalation, suppository or other pharmaceutically acceptable carrier and/or the mode of sending.
The accompanying drawing summary
Fig. 1 has described the aminoacid sequence of MMP2 enzyme.The selected aminoacid sequence that is used to suppress activity research is got up to be easy to identification by frame.Demonstrate the inhibition active aminoacid sequence TMRKPRCGNPDVAN of MMP2 (also by frame) as reference by other people (Loitta and colleague).
Fig. 2 has described the contrast restraining effect of the multiple oligopeptides of test.Use the Matrigel test, for human melanoma cancer cells A2058, oligopeptides PRKPKWDK blocks the cancer cells invasion and attack highly effectively.
Fig. 3 has described use Matrigel test, for human melanoma cancer cells A2058, and the restraining effect of oligopeptides PRKPKWDK aspect the invasion and attack of blocking-up cancer cells.
Fig. 4 has described use Matrigel test, for human breast cancer cell MCF7, and the restraining effect of oligopeptides PRKPKWDK aspect the invasion and attack of blocking-up cancer cells.
Detailed Description Of The Invention
Definition: as used herein, term " peptide " refers to comprise two or more by the covalently bound amino acid whose organic compound of peptide bond; Peptide can be dipeptides (it contains two amino acid residues), tripeptides (three amino acid etc.).
As used herein, term " oligopeptides " refers to contain the peptide that usually is less than 30 residue length. The length of oligopeptides is not critical for the present invention, as long as kept correct epi-position. Desirably, oligopeptides can be as far as possible little and still keep all in fact biologically actives of large oligopeptides, and its effectively blocking-up cancer cell invasion and attack and shifting.
" oligopeptides " is used interchangeably in this application with " synthetic peptide ". Used oligopeptides is " separation " but the synthetic peptide of " biology is pure " in the present invention.
As used herein, the one-letter symbol of amino acid residue is: A (alanine); R (arginine); N (asparagine); D (aspartic acid); C (cysteine); Q (glutamine); E (glutamic acid); G (glycine); H (histidine); I (isoleucine); L (leucine); K (lysine); M (methionine); F (phenylalanine); P (proline); S (serine); T (threonine); W (tryptophan); And Y (tyrosine).
Amino acid replacement is single residue normally. Displacement, disappearance, insertion or its any combination can join together to obtain oligopeptides. Conservative amino acid replacement comprises with the one or more amino acid of amino acid substitution with similar electric charge, size and/or hydrophobic character, for example glutamic acid (E)-aspartic acid (D) amino acid replacement. Nonconservative displacement comprises with having different electric charge, size and/or the one or more amino acid of hydrophobic amino acid substitution, for example glutamic acid (E)-valine (V) displacement. The present invention is intended to comprise the conservative change (displacement, disappearance, insertion or its any combination) of oligopeptides, needs only on the validity essence of blocking the cancer cell invasion and attack and shifting to change.
The people such as Rath (J Applied Nutr.44:62-69,1992; J Orthomolecular Med. 8:11-20,1993) supposition have high-hydrophilic to greatest extent the oligopeptides sequence of (high hydrophilicity maxima) and conformation and electric charge mediate the pathogenesis of various diseases. According to this supposition, the amino acid sequence of selecting in the mmp enzyme can be blocked by himself being attached to complementary series in the substrate effect of this enzyme. This design is different from Liotta and work together (U.S.Pat.No.5,372,809) described in detail fully, after the zinc molecule in the oligopeptides blocking-up enzyme wherein. Experimental evidence shows that the compound of albumen dissimilar in the cell can change the activity (Gavin and colleague, Nature 415:141-147,2002) of albumen in cell, and this has confirmed above supposition in itself. Be incorporated herein by reference with its integral body at this list of references of quoting.
In the present invention, we have identified the possible oligopeptides sequence in the MMP-2 amino acid sequence, and find that these oligopeptides sequences disturb the functional activity of MMP-2 effectively, use cancer cell at vitro invasion ECM as test model.
Not limit by any theory or mechanism of action, the invention provides the oligopeptides that effectively to block the cancer cell invasion and attack and shift.
A kind of mechanism of action may be that MMP-2 is combined with target ECM molecule by specific binding site. Therefore block these binding sites and can stop MMP-2 in conjunction with its ECM substrate molecule, suppress the destruction to ECM, thereby prevent that cancer and Other diseases diffusion from spreading all over whole body.
Identified the several potential binding site in the MMP-2 albumen, the synthetic analogues that the invention provides these oligopeptides sequences prevents that effectively ECM from destroying. A kind of therapeutic oligopeptides is PRKPKWDK, and it demonstrates the inhibition cancer cell invasion and attack and reaches about 90%.
The present invention also provides the therapeutical uses of oligopeptides in other MMP relevant disease. Because MMP-2 may come in conjunction with its target molecule among the ECM with identical site, disclosed oligopeptides can disturb Other diseases similarly in the present invention. Therefore, be not limited to cancer at prevention and the therapeutical uses of this synthetic oligopeptide required for protection, destroy the relevant pathological condition of ECM with other with MMP and also can be used for angiocardiopathy. These oligopeptides can be used as vaccine, are applied to the patient as injection, transfusion, inhalant, suppository or other pharmaceutically suitable carrier and/or the mode of sending.
The method of using peptide of the present invention and preparation adopts any approach in the multiple known method of administration, such as oral, IV, subcutaneous, transdermal and topical. The preferred method of the present invention adopts the pharmaceutical composition of parenteral.
The invention provides oligopeptides, it also can be used as vaccine to produce antibody, is used for test and relates to the disease of MMP (particularly MMP-2) with diagnosis, and by blood measuring or other suitable diagnostic assay, the progress of this disease of clinical monitoring or disappear.
The present invention relates to effectively block the synthetic peptide of cancer cell invasion and attack. The benefit of these materials and antibody thereof is the effectiveness in the clinical practice that is used for prevention and treatment invasive cancer and transfer. Preferably, has the amino acid whose synthetic oligopeptide of SEQ ID.2 for blocking-up invasive cancer and transfer. More preferably, synthetic peptide is included in the pharmaceutical preparation with blocking-up invasive cancer and transfer.
Described oligopeptides can be about 20 residues of about 6-. Most preferably, described oligopeptides is about 10 residues of about 8-. Most preferably, described synthetic oligopeptide contains the length of 8 amino acid residues.
Preferably, the concentration range of synthetic peptide is from 1 μ M to 500 μ M. Most preferably, the concentration range of synthetic peptide is from 50 μ M to 200 μ M.
Another object of the present invention be use described synthetic peptide as immunogene generating antibody, thereby the antibody of this generation can effectively be blocked invasive cancer and transfer.
Preferably, described synthetic peptide contains the length of 8 amino acid residues. Another object of the present invention is the immunogenicity oligopeptides that is included in the pharmaceutical composition, and described pharmaceutical composition comprises pharmaceutically suitable carrier and described oligopeptides. This oligopeptides can be used as vaccine. The pharmaceutical composition that comprises oligopeptides can be used for inducing for comprising have the oligopeptides sequence immune response of albumen of epi-position of (for example SEQ.ID.2).
Another object of the present invention be described composition and method in vivo with external realization.
The invention provides have with people MMP-2 albumen in the synthetic oligopeptide of the similar amino acid sequence of amino acid sequence.
The amino of described synthetic oligopeptide-and/or carboxyl-end can comprise respectively amino group (NH2) or carboxyl (COOH) group. Perhaps, described oligopeptides amino terminal can for example present hydrophobic grouping, includes but not limited to carbonyl benzyl (carbobenzyl), dansyl, tertbutyloxycarbonyl, capryl, naphthoyl (napthoyl) or other glycosyl group; Acetyl group; 9-fluorenyl methoxy-carbonyl (FMOC) group; Or amino acid residue modified, that non-natural exists. Perhaps, described synthetic oligopeptide carboxyl terminal can for example present the acylamino-group; Tertbutyloxycarbonyl; Or amino acid residue modified, that non-natural exists. Perhaps, the synthetic oligopeptide that the present invention includes the invasion and attack of blocking-up cancer cell and shift is by being omitted in the amino acid residue of N end or C end. The present invention also provides by the amino acid residue and do not consider of displacement among the given sequence and replaces the electric charge of residue and polarity and to the modification of the invasion and attack of blocking-up cancer cell and the oligopeptides that shifts.
Should understand the present invention and also conceive peptide analogues, wherein one or more amido links are optional to be replaced by the key except acid amides, the preferred acid amides that replaces or the isostere of acid amides. Therefore, although the amino acid residue in the peptide is generally described as amino acid, and the preferred embodiment of the invention is by the peptide illustration, those skilled in the art will recognize that, in containing the embodiment of non-amido link, term used herein " amino acid " or " residue " refer to structurally to carry the group of difunctional part with similar other of amino acid side chain. In addition, amino acid residue can also be closed or not sealing.
The invention provides the modification to blocking-up cancer cell invasion and attack and the oligopeptides that shifts, by repeating oligopeptides sequence one or repeatedly, each all is covalently bound to one or more oligopeptides and repeats in them.
The invention provides by intravenous use or with the upper acceptable approach of another kind treatment preventative or therapeutic use metabolism or the interaction that one or more described oligopeptides directly and competitively weaken or block MMP-2.
The invention provides preventative or therapeutic is used metabolism or the interaction that one or more described oligopeptides weaken or block MMP-2 indirectly, by subcutaneous application or in the acceptable mode of another kind used as stimulate the interactional specific immune response of metabolism that can partially or completely block MMP as vaccine. Preferred embodiment comprises MMP-2.
Preventative or the therapeutic that the invention provides one or more described oligopeptides is used, and wherein said oligopeptides is coupled to haptens to strengthen immune response, renders a service thereby increase treatment.
Preventative or the therapeutic that the invention provides one or more described oligopeptides is used, and its function stops or reduce the synthetic ratio of the MMP-2 albumen of cellular level with specificity as the feedback regulation thing.
The oligopeptides that the invention provides one or more cancer cells capable of blocking invasion and attack and shift as vaccine to produce specific antibody and be used to diagnose the progress of the disease that relates to MMP-2 or this disease of clinical monitoring or to disappear.
The invention provides the purposes of the oligopeptides of one or more blocking-up human diseasess, described disease includes but not limited to the cancer cells invasion and attack and shifts, and is used for prevention or treatment cancer; For example, prevention or treatment infectious diseases, cardiovascular disorder and degenerative disease.
The oligopeptides that the invention provides one or more blocking-up cancer cells invasion and attack and shift is used to prevent or treat the purposes of the disease that relates to MMP-2.
The purposes of the oligopeptides that the invention provides one or more blocking-up cancer cells invasion and attack and shift, wherein these oligopeptides can be used as vaccine, are applied to the patient as injection, transfusion, inhalation, suppository or other pharmaceutically acceptable carrier and/or the mode of sending.
Composition of the present invention can be at least a other material of form associating of peptide, and as stable compound, it can be used in any sterile biocompatible pharmaceutical carriers, and described carrier includes but not limited to salt solution, buffer saline, glucose and water.Described composition can be applied to the patient separately or with other material, medicine or hormons.Pharmaceutically acceptable carrier also can comprise vehicle and assistant agent, and it promotes that active compound is processed into pharmaceutically useful preparation.About the further details of preparation and medicine-feeding technology is found in " Remington ' sPharmaceutical Sciences " of latest edition, Mack Publishing Co., Easton, Pa., its content all is incorporated herein by reference.Pharmaceutical composition can be used as salt and provides, and can form with many acid, includes but not limited to hydrochloric acid, sulfuric acid, acetate, lactic acid, tartrate, oxysuccinic acid, succsinic acid etc.Salt tends to more be soluble in water-containing solvent or other protonic solvent than corresponding free alkali form.
The invention provides oligopeptides, it also can be used as vaccine and is used for measuring to generate antibody, is used for diagnosis and relates to the disease of MMP (particularly MMP-2) and the progress by blood measuring or other suitable this disease of diagnostic test clinical monitoring or disappear.
Following examples are intended to illustration enforcement of the present invention, and are not intended to the scope of the present invention that limits.
The oligopeptides sequence
Identify the amino acid whose high-hydrophilic of the relevant zone of enrichment electric charge aminoacid sequence of the MMP-2 in zone to greatest extent with software program identification.Oligopeptides of the present invention can the synthetic or preparation by technology well known in the art.(referring to for example Creighton, 1983, Proteins:Structures andMolecular Principles, W.H.Freeman and Co., N.Y.), it all is incorporated herein by reference.Prepare and be used for oligopeptides of the present invention and list in table 1.
These oligopeptides use " the Matrigel invasion and attack box of improvement " with migration by the restraining effect of Matrigel film to multiple cancer cells invasion and attack Matrigel, and (Becton Dickinson USA) estimates.Has the standard reference that the active oligopeptides TMRKPRCGNPDVAN of anti-MMP-2 is used as oligopeptides by Liotta with working together to demonstrate.
Table 1: the multiple oligopeptides sequence of identifying and being used for studying
Oligopeptides Sequence number
GDVAPKTDKE SEQ ID.1
PRKPKWDK SEQ ID.2
EDYDRDKKY SEQ ID.3
GRSDGLM SEQ ID.4
NYDDDRKW SEQ ID.5
LPPDVQRVD SEQ ID.6
RYNEVKKKMDP SEQ ID.7
The ordinary test condition
The oligopeptides customization of being identified is synthetic.Then they are used for Matrigel invasion and attack research.
(a) Matrigel invasion and attack research
(Becton Dickinson USA) carries out this research to use " the Matrigel invasion and attack box of improvement ".
In research, human fibroblasts-NHDF (Clonetics) is inoculated on " Matrigel " inset and it is reached converge the human melanoma cell.Do like this is in order to center on condition in the cancer cells body on every side in vivo near simulation.Then human melanoma cell A2058 is inoculated on the inset.The conditioned medium from fibroblast cell cultures that replenishes the selected oligopeptides of multiple level is added in the box.With about 24 hours of this system incubation.When incubation period finishes, wipe the cell on the inset upper surface.Count with " dyestuff fast " dyeing and at microscopically with the cell of having moved invading the Matrigel film to the inset lower surface.By comparing the cell count of not moving, calculate inhibition per-cent by film with contrast (oligopeptides of " 0 " level).The inhibition activity of contrast is considered to " 0 ".Reservation is used for zymogram studies from the substratum of invasion and attack test.
In the research of adopting human breast cancer cell MCF7, operation steps is substantially similar to melanoma cells used, replaces NHDF except adopting MRC5 (ATCC) inoblast.
In the research of adopting human breast cancer cell MDA-MB 231, with inoblast-MRC5 (ATCC) cell inoculation in the hole.All the other operations keep with identical to the research of MCF7 cell.
(b) zymogram studies
To put on " Novex " zymogram gels (Invitrogen) from the substratum (25-30 μ l) in each hole in the invasion and attack research.By what manufacturers was recommended gel is launched to develop and dyeing.Identify matrix metalloproteinase (MMP) based on its known molecular weight identification.
Embodiment 1
Multiple oligopeptides sequence is to the restraining effect of melanoma cells A2058 invasion and attack Matrigel and migration
The inhibition of oligopeptides (its aminoacid sequence is referring to table 1) to the invasion and attack of human melanoma cancer cells planted in test seven (7).Oligopeptides with aminoacid sequence PRKPKWDK demonstrates the blocking-up activity.Oligopeptides with TMRKPRCGNPDVAN demonstrates about 11% to be suppressed, and by contrast, PRKPKWDK demonstrates 73% and suppresses (Fig. 1).
Oligopeptides VI with aminoacid sequence LPPDVQRVD also has some blocking-up active (promptly about 20%).Oligopeptides " I " with aminoacid sequence GDVAPKTDKE does not demonstrate any activity (not being shown in Fig. 2) until 100 μ M concentration yet, with respect to the PRKPKVVDK of same concentrations show 63%.
Embodiment 2
Oligopeptides PRKPKWDK is to the restraining effect of melanoma cells A2058 invasion and attack Matrigel and migration
In these researchs, the concentration of PRKPKWDK in substratum changes between 0-150 μ M.Observe the invasion and attack (Fig. 3) that this oligopeptides suppresses melanoma cells progressively, about 37% from 50 μ M concentration is to 73% of 150 μ M.
The Matrigel film is similar to ECM, and cancer cells is broken through the ability that on behalf of cancer cells, the ability of the opposite side penetrate and migrate to film shift in vivo.Described oligopeptides can significantly reduce the invasion and attack of 3 kinds of dissimilar cancer cells.In this test system, activity is at ECM.We reach a conclusion, and our research has clearly show that thus described oligopeptides can disturb the degraded of ECM in the body, are that the progress of the sick disease of decreasing in basis has a negative impact to the disintegration of ECM wherein thus.
Embodiment 3
In these researchs, we have measured the restraining effect of PRKPKWDK to human breast cancer cell MCF7 (ATCC) invasion and attack Matrigel and migration.As to melanoma cells, these oligopeptides anticancer invasion and attack.Inhibition in 150 μ M concentration is about 70%.It increases to about 90% (Fig. 4) in 200 μ M concentration.
Embodiment 4
In these researchs, we have studied the inhibition activity of PRKPKWDK to another kind of human breast cancer cell-MDA-MB231.Inhibition in 150 μ M concentration is about 94%.
Embodiment 5
Whether next we estimated described oligopeptides can the effect of interferases after secretion.Zymogram studies does not show that PRKPKWDK is to any restraining effect (data not shown) by the amount of multiple cancer cells excretory MMP-2.
Several embodiments of the present invention have been described.Yet, should understand and can make multiple modification and do not depart from the spirit and scope of the invention.Therefore, other embodiment is within the application's scope of invention required for protection.
Although above carried out quite detailed elaboration, described sequence is non-limiting for explanation.Modification and improvement to above disclosed technology within those skilled in the art's limit of power comprise equivalent, are included within the scope of appended claim.It will be apparent for a person skilled in the art that and to make numerous modifications, change and variation, and not depart from inventive concept described here about details described above.For example, to the modification of basic sequence described here (chemistry or enzyme) also within the scope of the invention.For example, disclosed sequence can be dipeptides or tripeptides.And disclosed sequence can be modified, comprises this residue at the amino or the C-terminal of peptide.Described sequence can also be by chemically modified to increase its activity amidation of the C-terminal of sequence part (for example to).Described peptide can be by chemically modified to increase its activity (for example comprising glycine or alanine residue to the amidation of the C-terminal of sequence part or at arbitrary end).Therefore, should understand and can make multiple modification and do not depart from the spirit and scope of the invention, and this variation should be considered as the scope of following claims of the present invention within.
Sequence table
<110>MATTHIAS RATH
＜120〉method of synthetic peptide and treatment invasive cancer and transfer
<130>11957/23
<150>60/351,317
<151>January 23，2002
<160>7
<170>FastSEQ for Windows Version 3.0
<210>1
<211>10
<212>PRT
＜213〉homo sapiens (Homo Sapien)
<400>1
Gly Asp Val Ala Pro Lys Thr Asp Lys Glu
1 5 10
<210>2
<211>8
<212>PRT
＜213〉homo sapiens
<400>2
Pro Arg Lys Pro Lys Trp Asp Lys
1 5
<210>3
<211>9
<212>PRT
＜213〉homo sapiens
<400>3
Glu Asp Tyr Asp Arg Asp Lys Lys Tyr
1 5
<210>4
<211>7
<212>PRT
＜213〉homo sapiens
<400>4
Gly Arg Ser Asp Gly Leu Met
1 5
<210>5
<211>8
<212>PRT
＜213〉homo sapiens
<400>5
Asn Tyr Asp Asp Asp Arg Lys Trp
1 5
<210>6
<211>9
<212>PRT
＜213〉homo sapiens
<400>6
Leu Pro Pro Asp Val Gln Arg Val Asp
1 5
<210>7
<211>11
<212>PRT
＜213〉homo sapiens
<400>7
Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro
1 5 10

Claims (10)

1. oligopeptides comprises aminoacid sequence LPPDVQRVD (SEQ ID NO:6), and wherein said oligopeptides sequence length is a 8-10 amino-acid residue.
2. the peptide that comprises the oligopeptides of claim 1, wherein said oligopeptides is coupled to haptens and replys with enhancing immunity.
3. composition comprises the oligopeptides of claim 1 or the peptide of claim 2.
4. the composition of claim 3, wherein said composition is a pharmaceutical composition.
5. the composition of claim 3, wherein said composition is a diagnosis composition.
6. the composition of claim 3, wherein said composition is a vaccine.
7. the peptide of the oligopeptides of claim 1 or claim 2 is used to prepare the purposes of preventing or treating the pharmaceutical composition of cancer.
8. the purposes of claim 7, wherein said pharmaceutical composition is applied to the patient as vaccine as injection, transfusion, inhalation or suppository.
9. claim 7 or 8 purposes, wherein said oligopeptides or peptide are configured to the concentration of 1 μ M-500 μ M.
10. the purposes of claim 9, wherein said oligopeptides or peptide are configured to the concentration of 50 μ M-200 μ M.
CNA2007100054389A 2002-01-23 2003-01-23 Synthetic peptides and methods for treating cancer invasion and metastasis Pending CN101007844A (en)

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JP4911950B2 (en) * 2005-11-07 2012-04-04 晃 伊東 Cancer invasion / metastasis inhibitor using partial peptide of MMP-1
WO2010100282A1 (en) * 2009-03-06 2010-09-10 Universite Paris Descartes Method for treating cancer
US8593732B1 (en) * 2010-01-23 2013-11-26 Lightsmyth Technologies, Inc. Partially metallized total internal reflection immersion grating
US8003110B1 (en) * 2011-01-24 2011-08-23 Matthias W. Rath Metalloproteinase oligopeptides and their therapeutic use
EP2649985A1 (en) * 2012-04-13 2013-10-16 Lipotec, S.A. Compounds which inhibit neuronal exocytosis (III)
US20140017267A1 (en) * 2012-07-13 2014-01-16 Matthias W Rath Metalloproteinase oligopeptides and their therapeutic use

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